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Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches
  1. Frédérick Barreau1,2,
  2. Chrystèle Madre1,2,
  3. Ulrich Meinzer1,2,
  4. Dominique Berrebi2,3,
  5. Monique Dussaillant1,2,
  6. Françoise Merlin1,2,
  7. Lars Eckmann4,
  8. Mickael Karin5,
  9. Ghislaine Sterkers6,
  10. Stéphane Bonacorsi7,8,
  11. Thécla Lesuffleur1,2,
  12. Jean-Pierre Hugot1,2,9
  1. 1INSERM, U843, Paris, France
  2. 2UMR843, Université Paris Diderot, Paris, France
  3. 3Service d'anatomie pathologique, Hôpital Robert Debré, AP-HP, Paris, France
  4. 4Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA
  5. 5Laboratory of Gene Expression and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California, USA
  6. 6Service d'immunologie, Hôpital Robert Debré, AP-HP, Paris, France
  7. 7EA3105, Université Paris Diderot, Paris, France
  8. 8Service de microbiologie, Hôpital Robert Debré, AP-HP, Paris, France
  9. 9Service de gastroentérologie, Hôpital Robert Debré, AP-HP, Paris, France
  1. Correspondence to Professor Jean-Pierre Hugot, INSERM U843, Hopital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France; jean-pierre.hugot{at}


Nucleotide oligomerisation domain 2 (NOD2) mutations are associated with susceptibility to Crohn's disease and graft-versus-host disease, two human disorders related with dysfunctions of Peyer's patches (PPs). In Nod2−/− mice transcellular permeability and bacterial translocation are increased in PPs. In this study, we show that both anti-CD4+ and anti-interferon γ (anti-IFNγ) monoclonal antibodies abrogate this phenotype and reduce the expression of tumour necrosis factor (TNF) receptor 2 and the long isoform of myosin light chain kinase, thus demonstrating that immune T cells influence the epithelial functions. In turn, intraperitoneal injection of ML-7 (a myosin light chain kinase inhibitor) normalises the values of CD4+ T cells, IFNγ and TNFα. This reciprocal cross-talk is under the control of the gut microflora as shown by the normalisation of all parameters after antibiotic treatment. Toll-like receptor 2 (TLR2) and TLR4 expression were increased in Nod2−/− mice under basal conditions and TLR2 and TLR4 agonists induced an increased transcellular permeability in Nod2+/+ mice. Muramyldipeptide (a Nod2 agonist) or ML-7 was able to reverse this phenomenon. It thus appears that Nod2 modulates the cross-talk between CD4+ T cells and the epithelium recovering PP and that it downregulates the pro-inflammatory effect driven by the ileal microflora, likely by inhibiting the TLR pathways.

  • Nod2
  • Peyer's patch
  • MLCK
  • epithelial permeability
  • gut microflora
  • Crohn's disease
  • graft-versus-host disease
  • IBD
  • IBD basic research
  • immune response
  • CARD15
  • caspase recruitment domain 15
  • CD
  • Crohn's disease
  • DC
  • dendritic cell
  • FAE
  • follicle-associated epithelium
  • GALT
  • gut-associated lymphoid tissue
  • GVHD
  • graft-versus-host disease
  • LFs
  • lymphoid follicles
  • LPS
  • lipopolysaccharide
  • MDP
  • muramyl dipeptide
  • MLCK
  • myosin light chain kinase
  • NLRC2
  • natch Leucine-rich-repeat Card 2
  • NOD2
  • nucleotide oligomerisation domain 2
  • PGN
  • peptigoglycan
  • PP
  • Peyer's patches
  • Th1/2
  • T helper type 1/2
  • TLR
  • toll-like receptor
  • TNFR
  • TNF receptor

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  • See Editorial, p153

  • Supplementary figures and tables are published online only at

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  • Funding This work was supported by the Institut National de la Santé et de la Recherche Médicale, la Mairie de Paris, BREMICI, Association François Aupetit, Fondation pour la Recherche Médicale and the National Institute of Health.

  • Competing interests None.

  • Ethics approval The mice were housed in accordance with the institutional animal healthcare guidelines. The experiments were approved by the institutional committee for animal use.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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